Background: Mechanisms of postprandial hypoglycemia following gastric bypass (GB) surgery (PBH), remain incompletely understood. Thus, we aimed to assess the role of insulin secretion/beta-cell function (BCF), fractional hepatic insulin extraction (HE), insulin sensitivity (SI) and rate of glucose appearance (Ra) in patients with biochemically moderate and severe hypoglycemia. Methods: A total of 23 subjects with PBH (mean±SD age 41±12 years, BMI 28.1±6.1 kg/m2, 6.0±2.5 years since GB surgery) underwent an oral glucose tolerance test (75g of glucose), with frequent blood sampling for determination of glucose, insulin and C-peptide concentrations for up to 180minutes. Indices of BCF, HE, SI and Ra were calculated using the oral minimal model method and compared between subjects with nadir plasma glucose during the test below (severe hypo) and above 50mg/dL (moderate hypo). Results: Mean±SD nadir glucose was 43.3±6.0mg/dL in the severe hypo group and 60.1±9.1mg/dL in the moderate hypo group. Differences between the groups were found for indices of BCF, HE and Ra, whereas no significant differences were observed for SI (Figure 1). Conclusion: Present findings confirm three candidate mechanisms involved in PBH: increased BCF, diminished HE and faster Ra. Disclosure D. Herzig: None. M. Schiavon: None. A. Tripyla: None. V. Lehmann: None. J. Meier: None. S. Jainandunsing: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. L. Bally: None. Funding Swiss National Science Foundation (PCEGP3_186978); Italian Ministry of Education, University and Research (Law 232/2016); University of Padova; Diabetes Center Berne